CH625197A5 - Process for preparing verbenone, myrtenal and pinocarveol - Google Patents

Description

The present invention relates to a process for obtaining verbenone, blueberry and pinocarveol from oxidized terpenic mixtures. These compounds have therapeutic properties in bronchopulmonary diseases.

The preparation of verbenone and blueberry starting from a-cumene by oxidative autocatalysis in the presence of chromium salts, cobalt, etc., has been repeatedly described with yields of 15-20%. One of the reasons for the low reaction yields is the formation of collateral products of homolytic (radical) reaction such as verbenols and blueberries, alcohols which are not further oxidized to ketone in the specific reaction medium.

In the Swiss patent no. 542 163 of the same applicant describes a process for the preparation of terpene fractions, useful in the treatment of bronchopulmonary diseases, based on the oxidation of mixtures containing mainly a-pinene. In particular, with the process of the aforementioned Swiss patent, two terpene fractions are obtained, which distil respectively in the ranges of 40-60 ° C and 65-103 ° C.

It has now been found, and constitutes the object of the present invention, that these oxidation mixtures can be subjected to a further treatment which, in the case of the preparation of verbenone and blueberry, is a further oxidizing treatment with chromic anhydride in sulfuric acid, while in the case of pinocarveol, it consists in opening the oxiranic ring of the a-pinene-epoxide and subsequent transposition of the resulting compound.

It has in fact been found that in the case of verbenone and blueberry, the oxidizing treatment with chromic anhydride in sulfuric acid of the oxidation mixtures referred to in the aforementioned Swiss patent, the oxidative process continues with the total disappearance of the alcohols and the formation of compounds carbonyls (ketones and aldehydes). After the treatment with chromic anhydride in sulfuric acid, an isolation of the ketone bodies obtained by means of bisulfite complex and fractional distillation is carried out.

In the case of the pinocarveolus, the opening of the oxiranic ring is preferably carried out with isopropoxide aluminum, after which the carbonyl products are removed and the fractional distillation is carried out to isolate the pinocarveolus.

As regards the therapeutic use of the compounds obtained with the process of the present invention, the use in therapy of the terpene fractions described in the description of the Swiss patent n. 542 163. It has already been demonstrated that the therapeutic effect of fraction 2 of the aforementioned patent is attributable to the sonilo but of the pharmacological activities possessed by the individual components present in the mixture; it has also been shown that these pharmacological actions differ in their individual components not only quantitatively but also qualitatively.

15 It has now been found that the terpene compounds in question, in addition to some already known actions, such as antibacterial, balsamic and analectic, are also endowed with an effective anti-logistic and anti-aggregating action.

The demonstration of the pharmacological activity of verbe-20 none, pinocarveol and blueberry was based on the following data:

1) acute toxicity

2) action on the bronchial muscles

3) action on the inflammatory process

4) action on hemolysis

25 5) action on platelet aggregation 6) antibacterial action.

In all these tests, the activity of the various compounds was compared with that of fraction 2 of the aforementioned Swiss patent and with that of terpenic alcohol-based therapeutic preparations 30, in particular sobrerol.

Considering specifically the individual compounds objects of the present invention:

A-verbenone

35 The compound has shown to have a strong bronchodilator action for which it differs in a statistically significant way both from the other drugs present in fraction 2 of the Swiss patent 542 163 and from the reference terpene (sobrerol).

40 Due to this particular characteristic, it is believed that verbenone can be the active ingredient of a drug particularly indicated in the therapy of bronchopulmonary diseases accompanied by an obstruction of the respiratory tract of an inflammatory and infectious nature. 45 Verbenone also has medium intensity anti-inflammatory activity, has an anti-haemolytic action closely connected with a stabilizing action of cell membranes and finally also has a modest antibacterial action.

50 Furthermore, an anti-aggregating action is evident.

The activities of verbenone including the DL30 are summarized in the table below:

55 Tossi- Activity ìnSiT Activity Atticità

anti-flame p city- j.,, antibat-

Co1 "- actua emoliti- toria f '! A'a" terica ^ ggre-

DL5 or caEDso (4 hours) I "ce 200? 2? te

"G / kg 30 / ks" m, re / ml verbe-% ini-

none 115 639.5 biz.

29 (+)

+ + + + i +

+ + +

65

The dosage envisaged for therapeutic use is 10-50 mg / day, also valid for pinocarveol and blueberry.

3

625197

B-pinocarveolo

The compound has shown to have a strong anti-inflammatory action for which it differs statistically significantly from other drugs such as the mixture of fraction 2 of the aforementioned Swiss patent and compared to the reference terpene (sobrerol).

Due to this particular characteristic, pinocarveol can be the active ingredient of a drug particularly suitable for bronchopulmonary therapies accompanied by an intense inflammatory picture of the respiratory tract.

The pinocarveolus has a modest bronchodilator activity; it is also endowed with a marked anti-haemolytic action for which it can be attributed to this compound a stabilizing action at the level of cell membranes.

The pinocarveolus has a modest antibacterial action and also has an evident antiplatelet action.

The following table summarizes the activities of the pinocarveolus including the DL50.

The pharmaceutical compositions can be in the form of tablets, capsules, injectable ampoules, sprays in various forms of solution, ointments and creams, both as single components and in association with drugs indicated in these 5 diseases, i.e. antibacterial, antibiotic, chemotherapeutic, sulphonamides and anti-inflammatory, cortisone, analgesic.

The following examples are intended to illustrate in a non-limiting way the preparation of the compounds according to the present invention.

I

Example 1

Pinocarveolo compound

Activities

coughs

Activities

antiin city

anti flame actua emoliti toria

LD50

approx ED50

(4 hours)

mg / kg

Ug / ml

50

mg / kg

% ini-

biz.

140

132.3

41

(++)

Activities

bronchus-

dilatation

Do not smoke

62

IJ-g / ml

Antibacterial activity 200 txg / ml

Antiplatelet activity 100 Hg / ml

. + +

+ +

+ + +

C-mirtenale

This compound has shown to have a strong antibacterial action for which it differs statistically significantly from the terpene mixtures of fraction 2 of the Swiss patent and from other reference drugs.

Due to this particular characteristic, the blueberry is indicated as an active ingredient in drugs particularly indicated in bronchopulmonary therapy when an important bacterial component exists or in any case antibiotic therapy is required.

The blueberry has a modest anti-inflammatory action; it has an anti-haemolytic action and finally also has a bronchodilator-type action and an anti-aggregating action. The following table summarizes the activities of the blueberry, including the DL50.

m ..... -, v Attjyità Activities Activities

Tossi- Antun activity-. NPN. Activities ..

anti-flame-anti-bacterial actua emolithic? V? ta terica LD50 caEDso (4 hours)% ce 200? ™ te

- '<- 30 ixg / ml mg / kg ug / ml mg / kg

Ug / ml

Ug / ml blueberry 170

157.1

% ini-

biz.

30 (+)

+. +

+ + + + + +

Based on the results of the pharmacological tests, therapeutic applications in infectious or inflammatory diseases of the bronchopulmonary system, urogenital system, biliary tract and gastrointestinal system are contemplated for blueberry, pinocarveol and verbenone.

a) Oxidation of alcohols

100 g of terpenic mixture of fraction 2 of Swiss patent 15 no. 542 163, made up of 20-30% of carbonyl compounds (mainly verbenone and blueberry) and 50-60% of alcoholic compounds (mainly verbenol and blueberry) are dissolved in 2000 ml of dry acetone.

20 Separately, the oxidizing solution is prepared by carefully mixing 37.41 g of CrOa in 32.2 ml of concentrated H2SO4 and as enough water to obtain a final volume of exactly 140 ml.

25 The chromic acid is subsequently added drop by drop to the acetone solution under stirring, cooling in an ice bath so as to maintain the temperature always below 30 ° C.

Once the addition is complete, it is left to rest for 10 minutes, 30 is filtered on a celite panel and the filtrate is taken up again, evaporating the acetone under reduced pressure at 40 ° C.

The residue is diluted with water, cold neutralized with 10% NaOH and extracted with CHC13 until the water runs out.

35 The combined organic extracts are dried over anhydrous Na2SOé, filtered and concentrated to residue under reduced pressure to 40OIC.

In this way, about 100 g of crude product are obtained, made up of 50-60% of carbon-40 lica compounds (mainly verbenone and blueberry).

b) Separation of the carbonyl compounds from the oxidation crude

100 g of raw mi-45 obtained in stage a of the process are dissolved in a suitable container, dissolved in 500 ml of ether and a solution consisting of 120 g of NaHS03 and 72 g of NaHCOa in 2000 ml of water. It is vigorously beaten for about 20 hours at room temperature, transferred to a separating funnel and the organic phase is discarded.

50 The aqueous phase is washed with 2 X 500 ml of ether, after which the bisulfite aqueous solution is taken up again and subjected to steam distillation.

From the processing of the distillate 50-55 g of 55 mixture are obtained, practically consisting of pure verbenone and pure blueberry.

c) Obtaining pure verbenone and blueberry

50 g of product from the previous stage 60 are subjected to fractional distillation under vacuum at 20 mm Hg, using a reflux column filled with nickel shavings.

The distillation is carried out slowly (5-8 ml / hour) maintaining a reflux ratio of about 40: 1 during 65 the whole process.

The fraction that distills at 90-95 ° C at 20 mm Hg is made up of blueberry (19 g) and has the following chemical-physical characteristics:

625197

4

nD20 = 1.50 d20 = 0.98

IR = bands at 1684 cmr1 y C = 0 conjugated 1623 cm "1 y C = C conjugated 1471 cm-1- y C-H 1423-1387-1372

UV Anlal (ETOH) = 246 nm (and approximately 8400)

Semicarbazone: P. f. 210-215 ° C.

The fraction that subsequently distils at 110-113CC at 20 mm Hg is made up of verbenone (28.5 g) and has the following chemical-physical characteristics:

n ,, 20 = 1.49 d2 "= 0.97

IR bands at 1670 cm "1 y C = 0 conjugated 1615 cm-1 y C = C conjugated 1650-1435-1370

UV Xniai (EtOH) = 250 nm e = 7,300 Semicarbazone: P. f. 188-190 ° C.

Example 2

a) Transformation of a.-pinene epoxide into pinocarveol 60 g of terpene mixture of fraction 2 of Swiss patent no. 542 163, consisting of 10-15% of a-pinene epoxide, 20-30% of carbon-based compounds and 50-60% of alcohol-based compounds (ver-benol, pinocarveol and blueberry) , are dissolved in 60 ml of anhydrous toluene. An excess of aluminum isopropoxide (about 2-3 g) is added to the solution and boiled for 10 minutes. The mixture is cooled well and acidified slowly and carefully with diluted sulfuric acid, always keeping it at a temperature lower than or equal to 0 ° C. The phases are separated, the waters are exhausted with toluene, the organic solutions are combined, washed with water and dried on anhydrous Na2SO4. It is filtered and concentrated at 60 ° C under reduced pressure to a residue. About 60 g of crude product free of epoxides and enriched in compounds with an alcoholic function (pinocarveol, verbenol and blueenol) are obtained.

b) Separation of carbonyl compounds

5 The residue obtained in the previous stage is taken up with 300 ml of diethyl ether and the resulting solution is subjected to vigorous stirring with a mixture consisting of 60 g of NaHSOs, 36 g of NaHCOs and 1000 ml of water, the treatment being carried out for about 20 hours I at room temperature. It is transferred to a separating funnel and the phases are separated. The aqueous phase contains blueberry and verbenone in the form of soluble bisulphite adducts, from which pure products can be regenerated by operating as reported in the previous stages. The organic phase 15 containing the alcoholic compounds is washed to neutrality with water, dried over Na2SO4, filtered and concentrated to residue under reduced pressure. 40-45 g of residue are obtained mainly consisting of pinocarveol, verbenol and blueenol.

20

c) Obtaining pure pinocarveolus

The residue from the previous stage is subjected to a series of fractional distillations under vacuum, at 20 mm of Hg, using a reflux column filled 25 with nickel shavings.

The distillation is carried out slowly (5-6 ml / hour) maintaining a reflux ratio of about 40: 1 during the whole process.

The fraction which distills at 100-106 ° C at 20 mm of Hg 30 and which is strongly enriched in pinocarveolus is collected and subjected to a redistillation in the same conditions.

Approximately 15-18 g of 95-98% pure pinocarveol are obtained, having the following chemical-physical characteristics: 35 p. eb .: 103-104 ° C at 20 mm Hg nD20 = 1.4988 D42 «= 0.98

I.R. characteristic bands of double terminal bond at 6.00 n and 11.20 p ,.

v

Claims (4)

625197 1. Procedure for obtaining verbenone, mir-tenale and pinocarveol from oxidized terpene mixtures, characterized in that the mixture coming from the oxidation of a- and ß-pinene is subjected to an oxidizing treatment, after which it is carried out separation of the carbonyl compounds and isolation of the desired compounds by fractional distillation. 2. Process according to claim 1, characterized in that to obtain the verbenone and the blueberry, the oxidation of the oxidized terpene mixture is carried out with chromic anhydride in sulfuric acid and, after separation of the carbonyl compounds, fractional distillation is carried out taking the blueberry which distills at 90-95 ° C under a reduced pressure of 20 mm Hg and the verbenone which distills at 110-113 ° C at 20 mm Hg. 2 3. Process according to claim 1, characterized in that in order to obtain the pinocarveolus, the oxidized terpene mixture is treated with an excess of aluminum isopropoxide, after which the reaction product, deprived of the carbonyl compounds, is subjected to fractional distillation with withdrawal of the fraction which distills at 100-106 ° C under reduced pressure of 20 mm Hg made up of pinocarveolus. 4. Verbenone, pinocarveol and blueberry obtained with the process according to claim 1.